Sleep deprivation and sleep disorders are estimated to cost Americans over $100 billion annually in lost productivity, medical expenses, sick leave, and property and environmental damage. Narcolepsy is a disabling illness and a key to understanding other sleep disorders. Cataplexy is another major debilitating symptom of narcolepsy, and is estimated to affect 60 to 90% of narcoleptic patients. In the two decades since the discovery of its robust wake-promoting effect, modafinil has become the most widely used prescription drug for treatment of excessive sleepiness in narcolepsy and other sleep disorders. Its robust wake-promoting effect notwithstanding, modafinil fails to suppress cataplexy. This disadvantage of modafinil likely stems from its lack of activity at the norepinephrine transporter, the site of action for several potent cataplexy therapeutics. Compounds that are structurally related to modafinil, but exhibit novel pharmacological profiles with respect to norepinephrine transporter inhibition, may be of greater therapeutic value than modafinil itself. Acenta has established a compound library of nocaine/modafinil hybrid ligands that act as selective monoamine transporter inhibitors. The compounds vary in their potency as inhibitors of the cell membrane dopamine, norepinephrine and serotonin transporters (DAT, NET and SERT). Some of these novel compounds are potent, specific DAT inhibitors, while some others inhibit both DAT and NET with roughly equal potency. The diverse pharmacological profiles of these hybrid compounds provide a powerful resource for studies on the pharmacology of narcolepsy and of sleep/wake disorders in general. Through funding from this grant, we intend to follow-up on the exciting preliminary findings we have made with the following specific aims in pursuit of novel selective monoamine transporter inhibitors as potential therapeutics for excessive sleepiness and narcolepsy-cataplexy. The specific aims of this research proposal are: 1. Based on the compound library in hand, 12 potent trans-piperidine ligands possessing appropriate DAT and NET selectivity profiles will be resynthesized. Additionally, the cis-diastereomers of these selected compounds will also be synthesized and their monoamine transporter inhibitory activity will be investigated. 2. The dose-response curves of those selected compounds that exhibit good selectivity will be measured for the suppression of sleep attacks and cataplexy at the behavioral and electroencephalographic levels in hypocretin/ataxin-3 (hcrt/atax) mice. 3. Pre-clinical ADMET studies will be carried out on those compounds showing the greatest promise as potential therapeutics for excessive sleepiness and narcolepsy-cataplexy as determined in Aim 2. [unreadable] Public Health Relevance: Acenta Discovery has developed a compound library of piperidine-based nocaine/modafinil hybrid ligands that act as selective monoamine transporter inhibitors. The diverse pharmacological profiles of these hybrid compounds provide a powerful resource for studies on the pharmacology of narcolepsy and of sleep/wake disorders in general and the potential therapeutics for excessive sleepiness and narcolepsy-cataplexy. [unreadable] [unreadable] [unreadable]